Review question
What are the benefits and harms of ultra-radical (extensive) versus standard surgery in the management of ovarian cancer?
Background
The ovaries are small glands found on either side of the womb that produce and store eggs, and make hormones that control the menstrual cycle (periods). Ovarian cancer is the most common cause of death in women with a cancer of the reproductive system. Opinions differ about whether women with advanced ovarian cancer have better outcomes if they have 'ultra-radical' surgery, which is much more extensive than standard surgery, to remove tumours. Standard surgery in an advanced disease setting still has an element of radicality and comprises as a minimum many of the surgical procedures involved in more radical surgery. Ultra-radical (extensive) surgery is an extension of standard surgery and may include at least one additional extensive surgical procedure.
Review methods
We searched the scientific literature for studies comparing ultra-radical and standard surgery for women with advanced ovarian cancer. We looked for randomised controlled trials, which are regarded as the best type of study, and for non-randomised studies that were analysed using methods that allow for differences between the groups of women receiving different types of surgery.
Key results
We identified three non-randomised studies. The evidence is very limited and uncertain for all results since women were chosen to undergo each type of treatment, rather than randomly allocated, so there is a very high (critical) risk of bias in these types of studies.
In two studies (397 women), women who had radical surgery to remove the tumour may have 18% to 57% less chance of death compared to women who had standard surgery. The results were similar for women with more-extensive disease. There were very few deaths within 30 days of surgery. There may be less chance of disease progression with radical surgery.
One study compared radical versus standard surgery associated with both upfront primary (tumour removed before starting chemotherapy) and interval debulking (tumour removed between chemotherapy sessions) surgery on death, but the comparison was not fair and there was high risk of bias for reporting of outcomes.
One study (203 women) found that women who had radical procedures as part of upfront primary debulking surgery may have 8% to 58% less chance of disease progression or death compared to women who had standard surgery. The results were similar when including only the 139 women with more-extensive disease (where risk was 18% to 67% lower).
One analysis (527 women) merging radical surgery groups in one study found that women who underwent ultra-radical procedures (using both upfront primary and interval debulking surgical procedures) may be associated with 11% to 60% increased chance of disease progression or death than those who received standard surgery.
All studies were at very high (critical) risk of bias and we were very unsure about the evidence. We included relatively few women due to our stringent inclusion criteria. Studies either did not report or inadequately reported death, side effects or quality of life.
Main conclusions and certainty in the evidence
Although some of these results may suggest that survival may be better in women receiving upfront primary ultra-radical surgery rather than standard surgery, extreme caution is required with interpretation, as the studies were not well designed or analysed, and thus the effects could even be in the opposite direction.
We are unable to reach any definite conclusions about the relative benefits and harms of the two types of surgery. Better designed, large studies are needed.
We found only very low-certainty evidence comparing ultra-radical surgery and standard surgery in women with advanced ovarian cancer. The evidence was limited to retrospective, NRSs and so is at critical risk of bias. The results may suggest that ultra-radical surgery could result in improved OS, but results are based on very few women who were chosen to undergo each intervention, rather than a randomised study and intention-to-treat analysis, and so the evidence is very uncertain. Results for progression/DFS were inconsistent and evidence was sparse. QoL and morbidity was incompletely or not reported in the three included studies.
A separate prognostic review assessing residual disease as a prognostic factor in this area has been addressed elsewhere, which demonstrates the prognostic effect of macroscopic debulking to no macroscopic residual disease.
In order to aid existing guidelines, the role of ultra-radical surgery in the management of advanced-stage ovarian cancer could be addressed through the conduct of a sufficiently powered, RCT comparing ultra-radical and standard surgery, or well-designed NRSs, if this is not possible.
Ovarian cancer is the seventh most common cancer among women and the leading cause of death in women with gynaecological malignancies. Opinions differ regarding the role of ultra-radical (extensive) cytoreductive surgery in ovarian cancer treatment.
To evaluate the effectiveness and morbidity associated with ultra-radical/extensive surgery in the management of advanced-stage epithelial ovarian cancer.
We searched CENTRAL (2021, Issue 11), MEDLINE Ovid and Embase Ovid up to November 2021. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.
Randomised controlled trials (RCTs) or non-randomised studies (NRS), analysed using multivariate methods, that compared ultra-radical/extensive and standard surgery in women with advanced primary epithelial ovarian cancer.
Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed the risk of bias. We identified three NRS and conducted meta-analyses where possible.
We identified three retrospective observational studies for inclusion in the review. Two studies included women exclusively undergoing upfront primary debulking surgery (PDS) and the other study including both PDS and interval debulking surgical (IDS) procedures. All studies were at critical risk of bias due to retrospective and non-randomised study designs.
Meta-analysis of two studies, assessing 397 participants, found that women who underwent radical procedures, as part of PDS, may have a lower risk of mortality compared to women who underwent standard surgery (adjusted HR 0.60, 95% CI 0.43 to 0.82; I2 = 0%; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis including women with more-extensive disease (carcinomatosis) (adjusted HR 0.61, 95% CI 0.44 to 0.85; I2 = 0%; n = 283, very low-certainty evidence), but the evidence is very uncertain.
One study reported a comparison of radical versus standard surgical procedures associated with both PDS and IDS procedures, but a multivariate analysis was only undertaken for disease-free survival (DFS) and therefore the certainty of the evidence was not assessable for overall survival (OS) and remains very low. The lack of reporting of OS meant the study was at high risk of bias for selective reporting of outcomes.
One study, 203 participants, found that women who underwent radical procedures as part of PDS may have a lower risk of disease progression or death compared to women who underwent standard surgery (adjusted HR 0.62, 95% CI 0.42 to 0.92; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis in one study including women with carcinomatosis (adjusted HR 0.52, 95% CI 0.33 to 0.82; n = 139; very low-certainty evidence), but the evidence is very uncertain.
A combined analysis in one study found that women who underwent radical procedures (using both PDS and IDS) may have an increased chance of disease progression or death than those who received standard surgery (adjusted HR 1.60, 95% CI 1.11 to 2.31; I2 = 0%; n = 527; very low-certainty evidence), but the evidence is very uncertain. In absolute and unadjusted terms, the DFS was 19.3 months in the standard surgery group, 15.8 in the PDS group and 15.9 months in the IDS group.
All studies were at critical risk of bias and we only identified very low-certainty evidence for all outcomes reported in the review. Perioperative mortality, adverse events and quality of life (QoL) outcomes were either not reported or inadequately reported in the included studies. Two studies reported perioperative mortality (death within 30 days of surgery), but they did not use any statistical adjustment. In total, there were only four deaths within 30 days of surgery in both studies. All were observed in the standard surgery group, but we did not report a risk ratio (RR) to avoid potentially misleading results with so few deaths and very low-certainty evidence. Similarly, one study reported postoperative morbidity, but the authors did not use any statistical adjustment. Postoperative morbidity occurred more commonly in women who received ultra-radical surgery compared to standard surgery, but the certainty of the evidence was very low.